FIELD OF THE INVENTION
This invention is directed to a novel and improved chemical process and is particularly concerned with the production of the anxiolytic 1-[(dimethylamino)methyl]-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepines.
The process of this invention can be illustratively represented as follows: ##STR2## wherein R.sub.1 is hydrogen or alkyl of 1 to 3 carbon atoms, inclusive; wherein Y is nitrogen or C-R.sub.2 in which R.sub.2 is hydrogen, chloro, or fluoro; wherein R.sub.3 is hydrogen, fluoro, chloro, bromo, trifluoromethyl, or nitro; and wherein X.sup.- is the anion of a monovalent organic or inorganic acid, preferably the anions of hydrochloric, hydrobromic, and hydriodic and trifluoroacetic acid.
The novelty of this invention consists in using specific conditions with a specific reagent while applying a Mannich Type reaction to prepare as the major product compound of formula II. The use of Mannich reaction in this area is not new. Application Ser. No. 387,761, published Jan. 28, 1975, discloses the use of the Mannich reaction for the addition of a aminoalkyl group to a triazole ring. When the conditions of this disclosure are applied to the compounds of formula I of this invention the desired products of formula I are not obtained, but instead compounds of the formula III. ##STR3## Only with the present reagent IV and the conditions further on described the compounds of formula II are obtained. The reagent used has the formula IV; ##STR4## wherein X.sup.- is any suitable anion of a monovalent inorganic or organic acid such as hydrochloric, hydrobromic, hydriodic, trifluoroacetic, acetic, tetrafluoroboric, benzoic, HPF.sub.6, perchloric, chloric, HSbCl.sub.6 and the like. Such reagents are disclosed in the art, e.g. Bohme, H., et al., Chem. Ber. 105, 2233, (1972); Bohme, H., et al., Chem. Ber. 93, 1305 (1960), Bohme, H., Tetrahedron Lett. 2785 (1972); Volz, H. and Kiltz, H., Tetrahedron Lett. 1917 (1970) and Am. Chem. 752, 86 (1971); Huisgen, R., Kolbeck, W. Tetrahedron Lett. 783 (1965); Ahond, A. et al., J. Amer. Chem. Soc., 90, 5622 (1968); Jaser, Y., Chem. Comm. 253 (1974); Eschenmoser, A., et al., Angew. Chem. Int. Ed. (Eng) 10, 330, (1971).
In order to obtain a high yield in the reaction I.fwdarw. II specific reaction conditions must be applied. Under other conditions, the above described reagents can add at the 4-position only, or simultaneously in the 1- and 4-positions of compound I, thus providing products of lesser interest than those defined by formula II.
The present process is a considerable improvement over the process disclosed in application Ser. No. 505,342, filed Sept. 12, 1974, now U.S. Pat. No. 3,910,946.
In this patent the basic diazepine compound A is used to prepare a compound of formula II. This compound A has the generic structure. ##STR5## wherein Y and R.sub.3 have the same significance as in formula I.
Using the procedure of the above mentioned patent, 4 steps are necessary to obtain the corresponding compound of formula II above, in an overall yield of 11.7% (in II ##STR6## (R.sub.2 is 8-chloro). In addition a reagent is necessary, which is not commercially available and, as shown in the patent, requires 5 steps to be prepared. This reagent is of the formula B; ##STR7##
In the present process compound II (R.sub.3 is 8-chloro, Y is CH) is prepared from the corresponding compound A (R.sub.2 is 8-chloro) in 3 steps in an overall yield of 24% or better, with all reagents being commercially available.
In order to obtain a high yield in this reaction specific reaction conditions must be applied. Under other conditions, Bohme's reagent can add at the 4-position or in 1- and 4-positions of compound I providing products of lesser interest than those defined by formula II.